Article open access publication

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Nature Genetics, Springer Nature, ISSN 1061-4036

Volume 50, 7, 2018

DOI:10.1038/s41588-018-0132-x, Dimensions: pub.1104887944, PMC: PMC6314198, PMID: 29915430,

Authors

Wu, Lang (1)
Shi, Wei (2)
Wang, Qin (4)
Gusev, Alexander (6) (7) (8)
Auer, Paul L. (14) (15)
Benitez, Javier (17) (18)
Bermisheva, Marina (19) (20)
Blomqvist, Carl (21) (22)
Bojesen, Stig E. (24) (25) (26)
Brauch, Hiltrud (12) (27) (28)
Burwinkel, Barbara (12) (31)
Cox, David (41) (42)
Fasching, Peter A. (16) (54)
Figueroa, Jonine (29) (55)
Giles, Graham G (62) (63)
Hahnen, Eric (67) (68)
Hall, Per (44) (70)
Hunter, David J. (6) (72)
John, Esther M (75) (76)
Kosma, Veli-Matti (79) (80)
Kristensen, Vessela N. (81) (82) (83)
Lindström, Sara (15) (88)
Lo, Wing-Yee (27) (28)
Mannermaa, Arto (79) (80)
Manson, JoAnn E. (6) (92)
Nielsen, Sune F. (24) (25)
Nordestgaard, Børge G. (24) (25) (26)
Pylkäs, Katri (103) (104)
Rennert, Gad (106)
Romero, Atocha (32) (107)
Romm, Jane (47)
Scott, Rodney J (111) (112)
Smeets, Ann (100)
Spinelli, John J. (113) (114)
Stone, Jennifer (115) (116)
Surowy, Harald (12) (31)
Tamimi, Rulla M. (6) (52)
Taylor, Jack A (108) (117)
Torres, Diana (12) (120)
Winqvist, Robert (103) (104)
Xia, Lucy (69)
Ziv, Elad (123)
Milne, Roger L. (62) (63)
Zheng, Wei * (1)

* Corresponding author

Affiliations

Organisations

  1. (1) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
  2. (2) QIMR Berghofer Medical Research Institute, grid.1049.c
  3. (3) Cyprus Institute of Neurology and Genetics, grid.417705.0
  4. (4) University of Cambridge, grid.5335.0
  5. (5) Vanderbilt University, grid.152326.1
  6. (6) Harvard University, grid.38142.3c
  7. (7) Brigham and Women's Hospital, grid.62560.37
  8. (8) Dana-Farber Cancer Institute, grid.65499.37
  9. (9) Mount Sinai Hospital, grid.416166.2
  10. (10) University of Toronto, grid.17063.33
  11. (11) University of California, Irvine, grid.266093.8
  12. (12) German Cancer Research Center, grid.7497.d
  13. (13) Queen's University, grid.410356.5
  14. (14) University of Wisconsin–Milwaukee, grid.267468.9
  15. (15) Fred Hutchinson Cancer Research Center, grid.270240.3
  16. (16) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  17. (17) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  18. (18) Spanish National Cancer Research Centre, grid.7719.8
  19. (19) Institute of Biochemistry and Genetics of Ufa Scientific Centre, grid.429129.5
  20. (20) Hannover Medical School, grid.10423.34
  21. (21) Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  22. (22) Örebro University, grid.15895.30
  23. (23) N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
  24. (24) Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  25. (25) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  26. (26) University of Copenhagen, grid.5254.6, KU
  27. (27) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  28. (28) University of Tübingen, grid.10392.39
  29. (29) National Cancer Institute, grid.48336.3a
  30. (30) Lund University, grid.4514.4
  31. (31) Heidelberg University, grid.7700.0
  32. (32) Hospital Clínico San Carlos, grid.411068.a
  33. (33) American Cancer Society, grid.422418.9
  34. (34) Oncology and Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain
  35. (35) University Cancer Center Hamburg, grid.412315.0
  36. (36) University of Florida, grid.15276.37
  37. (37) University of Sydney, grid.1013.3
  38. (38) Erasmus University Medical Center, grid.5645.2
  39. (39) Antoni van Leeuwenhoek Hospital, grid.430814.a
  40. (40) Mayo Clinic, grid.66875.3a
  41. (41) Cancer Center of Lyon, grid.462282.8
  42. (42) Imperial College London, grid.7445.2
  43. (43) University of Sheffield, grid.11835.3e
  44. (44) Karolinska Institute, grid.4714.6
  45. (45) Temple University Health System, grid.412530.1
  46. (46) Leiden University Medical Center, grid.10419.3d
  47. (47) Johns Hopkins University, grid.21107.35
  48. (48) London School of Hygiene & Tropical Medicine, grid.8991.9
  49. (49) McGill University Health Centre, grid.63984.30
  50. (50) University of Westminster, grid.12896.34
  51. (51) University of Southampton, grid.5491.9
  52. (52) Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  53. (53) Leipzig University, grid.9647.c
  54. (54) University of California, Los Angeles, grid.19006.3e
  55. (55) University of Edinburgh, grid.4305.2
  56. (56) University Medical Center Hamburg-Eppendorf, grid.13648.38
  57. (57) Institute of Cancer Research, grid.18886.3f
  58. (58) Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  59. (59) Curtin University, grid.1032.0
  60. (60) Complejo Hospitalario Universitario de Santiago, grid.411048.8
  61. (61) University of California, San Diego, grid.266100.3
  62. (62) Cancer Council Victoria, grid.3263.4
  63. (63) University of Melbourne, grid.1008.9
  64. (64) McGill University, grid.14709.3b
  65. (65) University of Utah, grid.223827.e
  66. (66) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  67. (67) University Hospital Cologne, grid.411097.a
  68. (68) University of Cologne, grid.6190.e
  69. (69) University of Southern California, grid.42505.36
  70. (70) Stockholm South General Hospital, grid.416648.9
  71. (71) Frederick National Laboratory for Cancer Research, grid.418021.e
  72. (72) University of Oxford, grid.4991.5
  73. (73) Pomeranian Medical University, grid.107950.a
  74. (74) University Hospital Ulm, grid.410712.1
  75. (75) Cancer Prevention Institute of California, grid.280669.3
  76. (76) Stanford University, grid.168010.e
  77. (77) National University of Ireland, Galway, grid.6142.1
  78. (78) Bashkir State University, grid.77269.3d
  79. (79) Kuopio University Hospital, grid.410705.7
  80. (80) University of Eastern Finland, grid.9668.1
  81. (81) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
  82. (82) Oslo University Hospital, grid.55325.34
  83. (83) University of Oslo, grid.5510.1
  84. (84) Flanders Institute for Biotechnology, grid.11486.3a
  85. (85) KU Leuven, grid.5596.f
  86. (86) University of Hawaii at Manoa, grid.410445.0
  87. (87) Genome Institute of Singapore, grid.418377.e
  88. (88) University of Washington, grid.34477.33
  89. (89) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  90. (90) German Breast group, grid.434440.3
  91. (91) Macedonian Academy of Sciences and Arts, grid.419383.4
  92. (92) Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  93. (93) University Hospital of Heraklion, grid.412481.a
  94. (94) VU University Medical Center, grid.16872.3a
  95. (95) Technical University of Munich, grid.6936.a
  96. (96) University College London, grid.83440.3b
  97. (97) University Health Network, grid.231844.8
  98. (98) City Of Hope National Medical Center, grid.410425.6
  99. (99) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  100. (100) Universitair Ziekenhuis Leuven, grid.410569.f
  101. (101) Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, IL, USA
  102. (102) IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  103. (103) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland
  104. (104) University of Oulu, grid.10858.34
  105. (105) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  106. (106) Carmel Medical Center, grid.413469.d
  107. (107) Hospital Universitario Puerta de Hierro Majadahonda, grid.73221.35
  108. (108) Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
  109. (109) King's College London, grid.13097.3c
  110. (110) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  111. (111) John Hunter Hospital, grid.414724.0
  112. (112) University of Newcastle Australia, grid.266842.c
  113. (113) BC Cancer Agency, grid.248762.d
  114. (114) University of British Columbia, grid.17091.3e
  115. (115) Royal Women's Hospital, grid.416259.d
  116. (116) University of Western Australia, grid.1012.2
  117. (117) Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
  118. (118) Columbia University, grid.21729.3f
  119. (119) McGill University and Génome Québec Innovation Centre, grid.411640.6
  120. (120) Pontificia Universidad Javeriana, grid.41312.35
  121. (121) Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany
  122. (122) Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
  123. (123) University of California, San Francisco, grid.266102.1

Description

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

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University of Copenhagen

Danish Open Access Indicator

2018: Realized

Research area: Medicine

Danish Bibliometrics Indicator

2018: Level 3

Research area: Medicine

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Times Cited: 50

Field Citation Ratio (FCR): 19.88

Relative Citation ratio (RCR): 3.17

Open Access Info

Green, Accepted